SEPSIS

Inflammation Natural response of tissues to injury or infection aiming for body defence and tissue healing Acute inflammation is the response to acute injury, classically characterized by hotness, redness, pain, and swelling. The inflammation starts local with sequestration and activation of leukocytes and release of variety of inflammatory mediators from various cells. A delicate balance exists between pro- and anti-inflammatory mediators.

systemic inflammatory response syndrome (SIRS) Overwhelming infection (or injury) with excessive inflammatory response Local control of inflammation is lost Pro-inflammatory mediators are released to the circulation

Causes of SIRS Infection (sepsis) Trauma Acute pancreatitis Tissue necrosis Transfusion reaction Vasculitis Liver failure Disseminated malignancy

systemic inflammatory response syndrome (SIRS) SIRS is defined by the presence of two or more of the followings: Temperature > 38.0C or < 36.0C Heart rate > 90/min Respiratory rate > 20/min PaCO2 <32 mmHg (or mechanically ventilated) White blood count > 12  109/l or < 4 109/l

If “SIRS” is caused by infection the condition is called “sepsis”

Pathogenesis of sepsis Complex interaction between coagulation cascade, platelets, endothelial cells and white blood cells including: Activation of coagulation cascade Endothelial dysfunction Activation of neutrophils

Activation of coagulation cascade Pro-inflammatory mediators activate the coagulation pathway This is inhibited by natural coagulation inhibitors (antithrombin  and activated protein C (APC)) When natural anticoagulants are depleted (together with endothelial dysfunction), intravascular thrombosis and DIC develop

Activation of neutrophils Neutrophils adhere to the vascular endothelium Migrate through damaged endothelial cells to the interstitial space together with fluids and proteins resulting in tissue oedema Excessive fluid leak reduces intravascular volume, causing hypovolaemia.

Endothelial dysfunction Predispose to microvascular thrombosis and DIC Produce nitric oxide (NO) which is a potent vasodilator and myocardial depressor

Reduced oxygen uptake A major component of the pathophysiology of sepsis is the inability to take up oxygen at the mitochondrial level, even when the oxygen delivery is normal. The low oxygen extraction by the tissues raises plasma lactate and increases mixed venous oxygen saturation.

splanchnic hypoperfusion In patients with shock, splanchnic hypoperfusion and ischaemia is associated with: increased gut mucosal permeability translocation of microorganisms form the gut lumen into the portal and lymphatic circulation. kupffer cells activation with the production and release of inflammatory mediators that further amplify the inflammatory

SEPSIS APC Activation of coagulation cascade Endothelial dysfunction Neutrophiles activation and migration NO production Intra- vascular thrombosis interstitial oedema Vasodi- latation Myocadial depression MOF shock

Sepsis terminology Severe sepsis: sepsis with early organ dysfunction or hypotension Septic shock: sepsis associated with organ failure or severe hypotension unresponsive to fluid resuscitation MOF: represent multiple organ dysfunction syndrome

Multiple organ dysfunction syndrome (MOF) This can manifest in the lungs as acute respiratory distress syndrome (ARDS) or (ALI) kidneys as acute tubular necrosis (ATN) liver necrosis GIT ulceration and bleeding myocardial depression and heart failure disruption of coagulation (DIC)

Causative pathogenic microorganisms The vast majority of sepsis cases are caused by bacteria, both gram negative (most common) and gram positive (which is increasing). Fungi (esp. candida) are also important particularly in neutropenic patients. Viruses and protozoa are also possible causes of sepsis. Microbial bloodstream invasion, with positive blood culture is not essential for the development of sepsis as microbial products and toxins may illicit the same response.

Clinical features of sepsis Patients with sepsis may present with fever or hypothermia, tachycardia and warm extremities (until late in the course of the disease), and tachypnoea. Many patients are hypotensive, and may be in shock state. Apart from these manifestations, patients usually present with clinical features of the underlying infection, but many other patients do not show symptoms or signs that refer to the site of the infection.

Original site of infection in sepsis Common sites: The lungs (esp. nosocomial pneumonia, where gram negative bacilli are most common). The urinary tract (acute pyelonephritis). The bloodstream (central venous line infection). The abdomen (intra-abdominal abscess or necrotic gut complicating abdominal surgery).

Original site of infection in sepsis Less common sites include: The heart valves (endocarditis) The meninges (meningitis) The bones and joints (acute osteomyelitis and septic arthritis) The female genital tract (septic abortion and puerperal sepsis) The GIT (Cl. Difficele infection) The sinuses (sinusitis)

Investigation in patients with sepsis All patients require the following investigations: Culture of blood, sputum, urine, intravascular line, and wound discharge (blood culture is positive in only 10% of cases partly because of prior use of antibiotics) CBP (including WBC differential count and platelets) and ESR General urine examination Chest X-ray Coagulation profile (prothrombin time, APTT, and fibrinogen)

Investigation in patients with sepsis Other investigations will depend on the clinical picture including: X-ray of the bones, abdomen, and sinuses Ultrasound examination of abdomen and pelvis CT scan of the abdomen, pelvis or other sites Echocardiography (transthoracic and transoesophageal) CSF examination

Management of sepsis antibiotic therapy Prompt institution of appropriate antibiotic is essential. The antibiotic chosen should cover all the likely causative microorganisms. This would depend on: The probable site of the infection The known resistant pattern in the hospital Previous antibiotic therapy Any available culture results The antibiotics should be given intravenously, and in doses that ensure penetration to infected tissues (esp. in meningitis and endocarditis).

Management of sepsis Early goal-directed therapy (EGDT) is an algorithmic approach to hemodynamic optimization and resolution of global tissue hypoxia (aiming to normalize venous oxygen tension or lactate level) within the first 6 hours of disease presentation. This approach is globally adopted and was shown to reduce in-hospital mortality

Management of sepsis IV fluids and vasopressors Sufficient amounts of IV fluids should be given to replace the diminished intravascular volume. Early effective fluid replacement in the first 6 hours was shown to improve survival. Any crystalloid infusion is suitable, but normal saline is most commonly used. The amount to be given varies but it is usually around 6 liters. If the patient is still hypotensive despite IV fluid replacement, a vasoactive agent (vasopressors) has to be added. The choice is dopamine or noradrenalin given as IV infusion at a dose sufficient to keep blood pressure normal usually with inotropic drug (dobutamin)

Management of sepsis Source control Measures to eradicate the source of the infection are an integral component of therapy This may include: Abscess drainage Debridement of devitalized infected tissue Removal of infected prosthesis.

Management of sepsis other therapies The role of corticosteroid replacement therapy is controversial. Activated protein C is no more used in the treatment of sepsis